1. Field of the Invention
Aspects disclosed herein relate to fluorescence based reporter imaging, and more particularly to the use of temperature modulation in a scattering medium with high intensity focused ultrasound or any other form of radiation to modulate the optical signal emitted by temperature-sensitive optical reporters.
2. Description of the Related Art
High scattering in biological tissues does not permit optical imaging of fluorescence in thick tissue with high resolution. As one of the optical imaging techniques, fluorescence tomography (FT) utilizes laser light to excite the fluorescence sources located deep in a medium. Once excited, these sources relax to their ground state in nanoseconds by emitting lower energy photons. While propagating towards the surface of the medium, these photons are subject to a vast amount of scattering events along the way. This makes the FT inverse problem exceptionally difficult, and the FT inverse problem is defined as the problem of recovering the fluorescence source distribution from the measured light intensities on the tissue surface. Accordingly, the resolution and quantitative accuracy of the reconstructed images are very low2.
In the past, there has been extensive effort to improve the resolution of fluorescence tomography (FT). One approach is to integrate FT with other anatomic imaging modalities such as x-ray, MRI and ultrasound11-16. However, the weakness of this approach is that it does not perform well if the fluorescent target cannot be localized in the anatomical image. The low modulation efficiency and extremely low signal to noise ratio make the implementation of ultrasound modulation of fluorescence signals difficult3,4.
Meanwhile, an intriguing combination of optical and ultrasound techniques has led to the development of photo-acoustic tomography (PAT) that can provide the optical absorption maps with much higher resolution (˜1 mm) and a depth penetration of three to five centimeters1,17,18. PAT has been successfully applied to recover spatially resolved tissue intrinsic contrast maps with very high resolution. Although it can also provide distribution of exogenous contrast agents using multiple-wavelength measurements, PAT is inherently sensitive to absorption and detects differential increase in absorption due to molecular probes compared to background absorption19-21.
One proposed solution to this problem is to induce periodic displacement of scattering particles and variation of the refractive index in the medium using a focused ultrasound field. Using this approach and scanning the focused ultrasound field over the probed medium, ultrasound modulated fluorescence tomography (UMFT) can enhance the resolution3,4. However, only a small fraction of the photons that travels through the focused ultrasound column can be modulated at a time. The low modulation efficiency and extremely low signal to noise ratio (SNR) are the two main factors that make its implementation difficult.
Another proposed solution is to use micro-bubbles surface-loaded with self quenching fluorophores to enhance the contrast of UMFT5,6. However, some disadvantages of such microbubbles are their instability, low circulation residence times, low binding efficiency to the area of interest especially in the fast-flow conditions and possible side effects of their destruction during the imaging session7,8.